Breast cancer is the most common cancer among women, with significant morbidity and mortality. We hypothesize that variation in genes involved in insulin-like growth factor (IGF) signaling play a key role in breast cancer etiology. The IGF pathway regulates cell growth, and as uncontrolled cell growth is a hallmark of cancer, this pathway is a key component. We propose a comprehensive analysis of genes involved in IGF signaling through an approach that combines multiple variants in a single gene to form haplotypes and examines interactions of multiple genes in this important pathway. To investigate these associations, we will employ a two-stage approach. In the first stage, we will identify genetic variants significantly associated with breast cancer in a family-based association design of women with breast cancer and their unaffected female siblings, using existing resources of the Breast CFR and the kConFab. In the second stage, we will validate associations identified from the family-based design in a case-control design of population-based cases and controls. Our specific aims are: Aim 1 .To identify Single Nucleotide Polymorphisms (SNPs) in genes involved in IGF signaling and determine the haplotype tagging SNPs for genotyping that will maximize genetic information. Aim 2.To genotype SNPs selected in Aim 1 in the Caucasian breast cancer sibships. There are 2420 affecteds (cases) and 3118 unaffecteds (controls) in 3576 discordant sibling pairs (2126 sibships). Aim 3. To evaluate the association of haplotypes and SNPs in genes involved in IGF signaling and risk of breast cancer and age at diagnosis. We will analyze main effects, gene x gene interactions and gene x environment interactions. Epidemiological factors will include menopausal status, body mass index, physical activity, and exogenous hormone use. Aim 4.To validate significant associations of SNPs and haplotypes with breast cancer risk identified in Aim 3 using a set of 1900 Caucasian population-based cases and 1900 age-matched controls. We will further explore validated SNPs and haplotypes in African-American, Asian-American, and Hispanic discordant sibships. This study will address a critical and yet largely under-evaluated area in breast cancer research - the identification of genetic risk factors in a pathway central to the regulation of cell proliferation, a process underlying the development and progression of breast cancer. These results will provide information to more accurately assess breast cancer risk in women and to target women who could benefit from prevention strategies. Currently, chemotherapies are being directed to the IGF pathway and the results of this study could provide further targets, as well as assist in identifying the group of women who could particularly benefit from these new drugs.